Submissions for variant NM_007294.4(BRCA1):c.2426A>G (p.Glu809Gly)

dbSNP: rs397507201

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164846	SCV000215529	likely benign	Hereditary cancer-predisposing syndrome	2023-05-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086610	SCV000260562	likely benign	Hereditary breast ovarian cancer syndrome	2024-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700289	SCV000698951	uncertain significance	not specified	2024-06-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2426A>G (p.Glu809Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250572 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome, allowing no conclusion about variant significance. c.2426A>G has been reported in the literature in at least one individual affected with breast cancer (Darooei_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28231738). ClinVar contains an entry for this variant (Variation ID: 37468). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000164846	SCV000903581	likely benign	Hereditary cancer-predisposing syndrome	2017-05-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589185	SCV001470160	likely benign	not provided	2019-10-22	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000031049	SCV002004009	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001086610	SCV002025982	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164846	SCV003847672	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000031049	SCV004818181	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004700289	SCV005872192	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BP1_Strong
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589185	SCV005878178	benign	not provided	2024-07-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031049	SCV000053643	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-12-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504369	SCV000591385	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu809Gly variant was not identified in the literature, but was identified in dbSNP (ID: rs397507201) “with uncertain significance allele”, the COSMIC database in one sample, and the ClinVar database where it was classified with “Uncertain significance” by the Sharing Reports Clinical Project (derived from Myriad reports). The variant was not identified in any control populations, including the Exome Variant Server ESP project, the Exome Aggregation Consortium (ExAC) database, 1000 Genomes project, or HAPMAP populations. The variant was also not identified in any other databases searched, including the HGMD, UMD, LOVD and BIC databases. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Glu809 residue conserved across most mammals but is not conserved in lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.